Cu-based thin rolled foils: relationship among alloy composition, micromechanical and antiviral properties against SARS-CoV-2.

The healthcare-associated infections (HAIs) and pandemics caused by multidrug-resistant (MDR) and new-generation pathogens threaten the whole world community. Cu and its alloys have been attracting widespread interest as anti-contamination materials due to the rapid inactivation of MDR-superbugs and viruses. Applying thin Cu-based foils on pre-existing surfaces in hygiene-sensitive areas represents a quick, simple, cost-effective self-sanitising practice. However, the influence of chemical composition and microstructure should be deeply investigated when evaluating the antimicrobial capability and durability of Cu-based materials. The effect of composition on micromechanical and antiviral properties was investigated by comparing Cu15Zn and Cu18Ni20Zn (foil thickness from 13 to 27 µm) with Phosphorous High-Conductivity (PHC) Cu. The influence of recrystallisation annealing of PHC Cu was also investigated. Microstructural characterisation was carried out by optical (OM) and scanning electron (FEG-SEM) microscopy, Energy-dispersive Spectroscopy (EDS) and Electron-Backscattered Diffraction (EBSD). The micromechanical behaviour was assessed by microhardness, microscale abrasion and scratch tests. Cu-based foils were exposed to SARS-CoV-2 for different time points in quasi-dry conditions (artificial sweat solution), evaluating their antiviral capability by quantitative Reverse-Transcriptase Polymerase Chain Reaction (qRT-PCR). Surface morphology, contact angle measurements and Cu release were measured. All Cu-based surfaces completely inactivated SARS-CoV-2 in 10 min: pure Cu was the best option regarding antiviral efficiency, while Cu15Zn showed the best trade-off between micromechanical and antiviral properties.

New classes of antimuscarinic agents endowed with selective antispasmodic properties. 1-Arylsulfonyl pyrrolidin-2-ones and 2-thiones, 1-arylsulfonyl piperidin-2-ones and 2-thiones and 1-arylsulfonyl hexahydro-2H-azepin-2-one.

A series of 1-arylsulfonylpyrrolidin-2-ones (and 2-thiones), 1-aryl sulfonylpiperidin-2-ones (and 2-thiones) and 1-arylsulfonyl hexahydro-2H-azepin-2-one were synthesized and submitted to a battery of binding assays. The compounds showed little or no affinity for the receptors tested other than muscarinic receptors labelled either with [3H]pirenzepine or with [3H]quinuclidinyl benzilate. When tested in the isolated guinea pig ileum, they antagonized the contractions induced by acetylcholine and behaved as competitive muscarinic antagonists. After parenteral administration in mice, most compounds inhibited carbachol-induced diarrhoea but were less effective in counteracting salivation and lacrimation and showed little or no mydriatic action, thus displaying selectivity at the intestinal level. The reference drugs tested, atropine, butyl scopolamine and cimetropium bromide were far less selective. maximal in vivo activity was obtained by introducing diethylamino or 1-piperidino or 1-hexahydroazepinyl groups in the 4-position of the phenyl ring while the enlargement of a 5- to a 6-membered lactam ring or its conversion into a thiolactam had a less marked effect. The most interesting compounds were further evaluated for their ability to antagonize carbachol-induced colonic hypermotility in the rat and arecoline-induced analgesia in mice. The effect on gastric acid secretion in the rat was also investigated. The overall in vivo data showed that compounds 14, 15, 26 and 27, i.e. those bearing a 1-hexahydroazepinyl group in the 4-position of the phenyl ring, were the most potent and selective compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure-activity studies of 16-methoxy-16-methyl prostaglandins.

The synthesis of the pure diastereoisomer of 16-methoxy-16-methyl-PGF2 alpha, -PGE2, and -PGE1 is described. The absolute configuration of C-16 was established by chemical methods, while the absolute C-15 configurations of the diastereoisomers were assigned tentatively on the basis of their chromatographic behavior and NMR spectra. The synthetic prostaglandin analogues were evaluated for antisecretory, antifertility, and diarrheogenic effects. Both the C-15 and C-16 configurations were found to be critical for the biological activities. These studies indicate that the introduction of the methyl and methoxy groups at C-16 into the prostaglandin analogues markedly increases the ratio of antisecretory to diarrheogenic action. One of the PGE1 derivatives, 9f(15 alpha, 16R) (MDL 646, mexiprostil), was selected for further pharmacological evaluation and is currently under clinical investigation.

2-(1,1'-Biphenyl-4-yl)- 1,2,4-triazole[5,1-a] isoquinoline (L 14105), a potential orally active contragestational agent for the bitch: studies in the rat, hamster and dog.

In the search for second generation post-coital pregnancy terminating agents belonging to the class of 2-phenyl-triazole[5,1-a]isoquinolines, the contragestational profile of (1,1'-biphenyl)-4-yl-1,2,4-triazole[5,1-a]isoquinoline, referred to as L 14105, was investigated in hamsters, rats, and bitches. Following subcutaneous or intramuscular administration in oily vehicles, L 14105 shows a very high anti-fertility activity in the three animal species, being from 1.8 to 2.5 times more effective than the parent drug, DL 717-IT. Unlike DL 717-IT, L 14105 possesses a high activity when administered by the oral route. The results obtained in the bitch make it confirm its potential use as a new orally active agent for the interruption of unwanted pregnancies.

The rate of N-demethylation of N,N-dimethylanilines and N-methylanilines by rat-liver microsomes is related to their first ionization potential, their lipophilicity and to a steric bulk factor.

The N-demethylation of a series of 12 p-substituted N,N-dimethylanilines, nine m-substituted N,N-dimethylanilines, one o-substituted N,N-dimethylaniline and four p-substituted N-methylanilines by rat-liver microsomes was studied. For each compound, the apparent Vmax and Km values were determined and these parameters were correlated with their electronic, lipophilicity and steric bulk parameters reported in the literature. Multi-parameter linear regression analysis showed a good correlation between log Vmax and these parameters for the p-substituted N,N,-dimethylanilines. A lower degree of correlation was observed with the meta-substituted N,N-dimethylanilines.

Zetidoline metabolism by rat liver microsomes. Formation of metabolites with potential neuroleptic activity.

1-(3'-Chlorophenyl)-3-[2-(3,3-dimethyl-1-azetidinyl)ethyl] imidazolidin-2-one, zetidoline, a new neuroleptic agent, when incubated with rat liver microsomes was rapidly metabolized to six free (mets B, D, I, L, M and N) and two conjugated metabolites (mets E and F). Sites of the metabolic attack (oxidation) were primarily the aromatic moiety, then the imidazolidinone and the azetidine rings. The metabolites were purified and structures assigned by means of EI-MS, 1H-NMR and chemical synthesis (mets B, D, L and M). The main metabolites, zetidoline, some chemical analogues and a few known dopamine antagonists were tested as in vitro inhibitors of 3H-zetidoline and 3H-spiperone binding to rat striatal membranes, and as in vivo inducers of prolactin release in female rats (inhibition of the estrus cycle). Two zetidoline metabolites, namely 4'-hydroxy zetidoline (met. B) and 5-hydroxy zetidoline (met. L), were found to have both in vitro and in vivo activities comparable to those of the parent drug. Identification of these active hydroxylated metabolites appears important both in the search of new leads of neuroleptics and for designing pro-drugs derivatives with improved pharmacokinetic profiles.

Biochemical characterization of the hepatic effects in mice and rats of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a hepatic neoplasm promoter.

The biochemical effects on the liver of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), a phenobarbital-like enzyme inducer, were studied in the mouse and rat. In mice a single dose of TCPOBOP (3 mg/kg, ip) caused marked and long-lasting (at least 7 days) induction of liver cytochrome P-450, 7-ethoxycoumarin-O-deethylase, and epoxide hydrolase. TCPOBOP had much less effect in rats than in mice, even at a higher dose (30 mg/kg) TCPOBOP also induced DNA synthesis in mice and rats but ornithine decarboxylase activity only in mice. In addition, in mice but not in rats, TCPOBOP increased microsomal membrane fluidity, as detected by fluorescence polarization measurements.

On the mode of action of a new contragestational agent (DL 111-IT).

Non-hormonal compounds belonging to 3,5-diphenyl-1H,1,2,4 triazoles and chemically related classes (triazoles in short) are known to be endowed with high contragestational activity in rodents, dogs and primates. The data herein reported for one of the leaders of this family of compounds (DL 111-IT) along with those previously reported for some analogues, demonstrate that triazoles cause pregnancy arrest by a direct action on conception product. This action is expressed through a progressive slowing down of the conceptus development with a consequent onset of a state of anoxia, pregnancy arrest, degeneration of placentae and adnexae and their absorption or expulsion. The selective time of gestation during which they elicit the antifertility effect (early post-implantation period) and the histological examinations revealed that the target of their action are the ectoplacental and decidual cells. Biochemical studies on conceptus product demonstrate that, although they do not bind to progesterone receptors or inhibit ornithine decarboxylase activity, triazoles induce an early and marked increase in the number of cytosol progesterone receptors accompanied by a steep decrease in the ornithine decarboxylase activity in the product of conception. These findings are discussed in relation to the possibility that triazoles may trigger pregnancy arrest by interfering with the chain of events by which progesterone regulates the mitotic activity of decidual and trophoblastic cells.

Highly selective antiinflammatory and analgesic activity of 3-(1-methylethyl)-2-(4-methoxyphenyl)-3H-naphth[1,2-d]imidazole, a new non-acidic molecule.

3-(1-Methylethyl)-2-(4-methoxyphenyl)-3H-naphth[1,2-d] imidazole (MDL-035) has antiinflammatory activity in various antiinflammatory models such as carrageenin and nystatin oedemas, cotton pellet granuloma and adjuvant arthritis. The antiinflammatory potency of MDL-035 is greater than that of acetylsalicylic acid and phenylbutazone, but lower than that of indomethacin. MDL-035 has practically no gastroulcerogenic activity in rats, does not affect water or salt excretion, has no hormonal or antihormonal effects and has no other unwanted pharmacological effects. Its acute toxicity is very low.

Immunological profile of DL111-IT, a new immunosuppressant agent.

The immunosuppressive properties of the non-hormonal contragestional agent 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (DL111-IT) were evaluated on different immunological functions. The compound displayed significant immunosuppressive activity on both humoral and cellular immunity when administered during the inductive phase of the immune response. In experimental models autoimmunity and skin transplantation, DL111-IT was able to reduce the production of auto-antibodies and prolong skin graft survival. The compound, even at doses much higher than those effective inhibiting immune responses, did not influence the survival time of some haematological tumors in mice. This suggest that DL111-IT does not act by a general cytotoxic mechanism.

Biliverdin as an electron transfer catalyst for superoxide ion in aqueous medium.

Stopped flow experiments gave evidence of the formation of a biliverdin-superoxide complex and/or a biliverdin radical anion by reaction of aqueous O2- with biliverdin. Such transient species are likely intermediates both in the bleaching of biliverdin, during exposure to the aerobic xanthine oxidase reaction, and in the reduction of ferricytochrome c under the same conditions.

In vivo stereospecific [3H]spiperone binding in rat brain: characteristics, regional distribution, kinetics and pharmacological properties.

The time course of [3H]spiperone distribution in the three major pools (specifically and non-specifically membrane-bound and soluble) of different brain areas, was studied in rats given a tracer amount of the drug. In addition, the stereospecificity, dissociation kinetics and pharmacological nature of the in vivo bound [3H]spiperone were investigated. The data show that [3H]spiperone binding sites in the striatum, olfactory tubercles and hypophysis differ clearly from those of the cortical regions. In the prevalently dopaminergic areas the amount of ligand bound to membranes is, up to 24 h post-treatment, proportional to the total 3H present. However a more correct analysis of the data was obtained in all the experiments when membrane-bound was measured instead of total radioactivity. Thus assay of the in vivo specifically bound [3H]spiperone appears essential for a correct evaluation of the density, affinity, regional distribution, pharmacological nature and kinetics of the drug-receptor interaction.

Characterization of [3H]zetidoline binding to rat striatal membranes.

The binding of [3H]zetidoline, a novel neuroleptic agent, to rat brain striatal membranes was investigated in-vitro. The optimal binding conditions for [3H]zetidoline differed from those for [3H]spiperone in pH, temperature and time. [3H]Zetidoline has high affinity for striatal dopamine receptors. Its binding is saturable, stereo-specific, has a low non-specific component and is reversible and tissue specific. The Scatchard analysis gave a biphasic curve, indicating that [3H]zetidoline interacts with more than one population of receptor sites (B'max = 67 fmol mg-1 protein, K'd = 0.11 nM; B"max = 500 fmol mg-1 protein, K'd = 2.49 nM). Kinetic analysis of rates of association and dissociation yielded a Kd value in agreement with that measured at equilibrium. Inhibition studies indicated that only dopamine and dopaminergic agents are able to displace [3H]zetidoline from its binding sites, and in a different rank order from that for displacement of [3H]spiperone. (-)-Sulpiride was especially effective in inhibiting [3H]zetidoline specific binding. Furthermore, like that of [3H]benzamides, [3H]zetidoline binding appears to be highly Na+-dependent and Li+ only partially substitutes Na+.

Promoting effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene in mouse hepatocarcinogenesis.

The effects of phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on liver hyperplasia, induction of microsomal enzyme activities, and two-stage hepatocarcinogenesis were evaluated in B6C3F1 female mice. For 4 weeks four groups of mice received PB (500 p.p.m. in the drinking water), TCPOBOP (3 mg/kg i.p. once every week), PB together with TCPOBOP or corn oil vehicle i.p. TCPOBOP induced liver hyperplasia and hypertrophy and increased p-nitroanisole-O-demethylase and aminopyrine-N-demethylase more than PB. Neither chemical changed UDPG-transferase activity. The association of PB and TCPOBOP gave the same effects as TCPOBOP alone. Other four groups of mice were treated with N-nitroso-N-diethylamine at 7 days of age and then, starting from 8 weeks of age, received the above specified weekly treatments for 20 weeks and were then sacrificed. Hepatocellular nodules greater than 150 microns were found in all animals of all groups. Due to increased size of the liver compared to controls, the number of nodules/cm3 decreased after PB and TCPOBOP treatments given alone or together; however the mean volume of nodules and the percentage of liver volume occupied by nodules increased after TCPOBOP but not after BP treatment, and the association of PB and TCPOBOP was even more effective than TCPOBOP alone. Hepatocellular adenomas greater than 2.4 mm in diameter were observed in 5 of 10 TCPOBOP-treated mice (total of 11 nodules) and in 5 of 11 mice that received PB plus TCPOBOP (total of 15 nodules). Hepatocellular carcinomas were seen in one mouse treated with PB and in three mice given PB and TCPOBOP.

Contragestational profile of the tumor-inhibiting agent, L-alanosine, in the rat and the hamster.

L-Alanosine [L-2-amino-3(N-hydroxy-N-nitrosamino)propionic acid], a tumor-inhibiting agent, induces pregnancy arrest after single or multiple SC or PO administration to rats and hamsters. Its contragestational effects are dose- and route-dependent, with no important differences in species-sensitivity or administration schedules. L-Alanosine is maximally effective shortly (3-4 days) after implantation. Both placenta and fetus appear to be target tissues. Consistent with previous in vitro findings, adenine but not aspartic acid counteracts the contragestational action of L-alanosine. The 'contragestational test', i.e., the effect on conceptus growth, appears to be an interesting approach for learning more about the antiproliferative activity of an antineoplastic agent.

Structure reactivity relationships in the microsomal oxidation of tertiary amines.

Apparent kinetic parameters Vmax and KM have been measured for the oxidative N-demethylation of twelve para-substituted N, N-dimethylanilines catalysed by rat liver microsomes. Vmax was enhanced by pretreatment of the rats with phenobarbital, whereas pretreatment with beta-naphthoflavone gave no appreciable enhancement. In the case of phenobarbital pretreatment the kinetic parameters could be expressed in terms of lipophilic and electronic effect of the substituents. Kinetic parameters from control and beta-naphthoflavone microsomes gave no statistically meaningful correlation.

Metabolic pathways of the contragestational agent, 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (DL 111-IT), in the rat.

The metabolic pathways of the non-hormonal anti-fertility agent 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (DL 111-IT) were studied in rats given the 14C-labelled compound intramuscularly. The diaryltriazole, once absorbed, was metabolized rapidly by three phase I reactions: (a) hydroxylation at the C-4 of the methoxyphenyl ring, (b) hydroxylation at the alpha-C of the ethyl chain, and (c) demethylation of the methoxyl function. Seven free metabolites and three conjugates have been isolated and characterized by u.v., i.r., n.m.r. and mass spectroscopy. The products of the first step of metabolism of the diaryltriazole were tested for their pregnancy-terminating activity in the rat. They were only 5-9% as effective as the parent compound, indicating that the unchanged drug is the active molecule.

Studies on the luteolytic activity of MDL-646, a new gastroprotective PGE1 analogue, in the hamster.

MDL-646, 11,15-dihydroxy-16-methyl-16-methoxy-9-oxo- prost -13-en-1-oic acid methyl ester, is one of the most active members of a new class of PGE1 analogues with potent gastric cytoprotective and antisecretory activity. The potential luteolytic activities of MDL-646 and its corresponding PGE2 derivative, L 14224 were assessed from their ability to terminate pregnancy and to reduce plasma progesterone levels in the hamster. PGE1 and PGE2 were used as reference compounds. The biological and biochemical data clearly demonstrate that these 16-methyl-16-methoxy PGE derivatives, given s.c. or p.o. either once or for 3 days, have no luteolytic effects up to a daily dose of 2-2.5 mg/kg, and are therefore at most 1/2 to 1/4 as luteolytic as the parent natural PGEs. The dissociation between gastroprotective and luteolytic activity was interpreted to indicate that these new PGE derivatives have a specific action.

Prolactin-releasing effect of zetidoline, a new neuroleptic agent, in the rat.

The effect of a new neuroleptic agent, zetidoline, 1-(3-chlorophenyl)-3-[2-(3,3-dimethyl-l-azetidinyl)ethyl]imidaz olidin-2-one (ZET), on prolactin release was studied in both male and female rats and compared to that of the classic antipsychotic drugs chlorpromazine and haloperidol. Time-course and dose-effect studies showed that ZET induces a rapid and short lasting increase in plasma prolactin levels, with a significant increase after a dose as low as 0.33 mg/kg, i.p.. The overall patterns of prolactin release appeared to be similar in both sexes but the response was markedly greater in females than in males. The prolactin-releasing effect of ZET was counteracted by apomorphine and L-dopa, which indicates that blockade of dopamine receptors is the basis of its neuroendocrine action. As a prolactin-releaser, ZET was found to be about 5 times as potent as chlorpromazine and about one-ninth as potent as haloperidol.